Docetaxel for Gastric and Esophageal Carcinomas

ABSTRACT: Docetaxel (Taxotere) has been successfully investigated in the therapy for advanced gastroesophageal tumors as both a single agent and in combination regimens. As a single agent, phase II study results demonstrate an overall response rate of 17% to 24%, with occasional complete responses in a disease in which complete responses are rare. These figures classify docetaxel among the most active agents for the disease. Further research initiatives in gastric cancer have evaluated the combined use of docetaxel with traditionally established agents, such as cisplatin and fluorouracil (5-FU). The rationales for the combined use of docetaxel with these agents include the in vitro demonstration of a lack of complete cross-resistance and nonoverlapping side-effect profiles. Phase II study results of docetaxel-based combinations demonstrate high overall response rates and progression-free survival, comparable with results obtained with established three- and four-drug regimens. Therapy is generally well tolerated, with a predominant toxicity of hematologic neutropenia. Docetaxel-based combination regimens are currently undergoing evaluation in randomized phase III trials in comparison with established standard regimens. While previous combination chemotherapy regimens have failed to improve survival over single-agent therapy, the aim for incorporation of docetaxel with other active agents is to improve palliation and possibly survival of patients with gastric cancer. [ONCOLOGY 16(Suppl 6):89-96, 2002]

Despite a decline in the incidence of gastric carcinoma in industrialized countries, gastric cancer remains the second most common cause of cancer-related deaths worldwide.[1] Chemotherapy can provide significant palliation of symptoms for patients with unresectable, locally advanced, or metastatic disease. Single agents that produce partial response rates of up to 20% (fluorouracil [5-FU], cisplatin, doxorubicin, and mitomycin [Mutamycin]) are considered the most active in gastrointestinal cancers.[2] Combination regimens employing these agents result in higher response rates (30%-50%), but are associated with a greater degree of toxicity and produce similar overall survival (ranging from 6-10 months), as compared with single-agent therapy.[2] The identification of new active agents is therefore essential if prolongation of patient survival is to be attained. The search for novel, more active agents prompted investigation of docetaxel (Taxotere) in this disease.

Docetaxel is a semisynthetic taxoid diterpene derived from the needles of the European yew tree called Taxus baccata.[3] Docetaxel belongs to the family of drugs called taxanes, which act as mitotic spindle poisons, promoting tubulin polymerization while inhibiting depolymerization of microtubules.[4,5] Docetaxel has shown extensive cytotoxic activity in animal models, as well as antitumor activity against a variety of common cancers in clinical studies.

To evaluate the antitumor effects of docetaxel against gastric tumors, investigators from Japan utilized in vitro chemosensitivity tests and in vivo human tumor xenografts.[6] The in vitro assay revealed that docetaxel was more active than paclitaxel in six of the nine cultured human gastric cancer cell lines, and its cytotoxicity was 2 to 80 times greater than that of paclitaxel. To confirm the in vitro results, the chemosensitivity of different tumor specimens was tested using an in vivo assay. Results demonstrated that docetaxel was active in well-differentiated, poorly differentiated, and undifferentiated gastric cancers. Docetaxel demonstrated a cytotoxic effect in 10 of the 18 clinical specimens (56%)-an effectiveness rate similar to that of cisplatin (50%) on the same specimens. The investigators concluded that based upon the in vitro and in vivo findings, docetaxel was anticipated to be a novel, clinically useful anticancer drug for gastric cancer with a unique mechanism of action and broad spectrum of antitumor activity.

Numerous clinical studies of docetaxel for gastroesophageal cancer have now been conducted. The findings demonstrate that the in vivo and in vitro tumor chemosensitivity screening tests accurately predicted the notable antitumor activity of docetaxel. The remainder of this manuscript will review the results of clinical studies of docetaxel for upper gastrointestinal cancers. Docetaxel has been studied in first- and second-line treatment of gastric and esophageal cancers as a single agent, and, subsequently, in combination chemotherapy regimens and as part of a combined-modality therapeutic approach. The encouraging results obtained with docetaxel in phase I and phase II studies led to large, comparative phase III trials for gastroesophageal cancers, the results of which are eagerly awaited.

Single-Agent Docetaxel for Gastric Carcinoma

Single-agent docetaxel has been studied in previously untreated gastric cancer in phase II trials in the North America, Europe, and Asia. As a single agent, docetaxel has produced response rates ranging from 17% to 24%.[7-10] This level of response in untreated patients is considered significant and classifies docetaxel among the most active chemotherapeutic agents in this disease. Table 1 summarizes the single-agent trials of docetaxel in previously untreated advanced gastric carcinoma patients.[7-10]

Sulkes et al[7] reported a European Organization for Research and Treatment of Cancer (EORTC) phase II trial in 37 patients with previously untreated advanced gastric cancer given 100 mg/m² of docetaxel every 3 weeks. Among 33 evaluable patients, 24% achieved a partial response for a median duration of 7.5 months. An additional 11 patients had stabilization of their disease. A median of four cycles of chemotherapy were delivered to patients (range: 1-8) for a total of 156 courses. Docetaxel dose reduction was necessary in 30 cycles (19%), mainly because of myelosuppression or skin toxicity. The major toxicity reported was noncumulative grade 3/4 neutropenia (95%); this rarely resulted in febrile neutropenia (5%) or sepsis, (0%) however. Prophylactic steroid premedication was not routinely administered and therefore resulted in nonhematologic toxicities, including hypersensitivity reactions (24%) and fluid retention (22%). As a result of the 24% response rate, the authors concluded that docetaxel was an active agent in advanced gastric cancer that warranted further clinical investigation.

Taguchi and colleagues conducted a phase II study of single-agent docetaxel, 60 mg/m² every 3 weeks, in patients with advanced, measurable, or evaluable gastric cancer.[8] Docetaxel dose escalation or reduction was planned according to hematologic and nonhematologic toxicities experienced in the previous course. A total of 57 patients entered the study, with 45 patients evaluable for response and 53 patients evaluable for toxicity. An overall response rate of 22.2% was observed, including one complete response and nine partial responses. Toxicities included grade 3/4 leukopenia (53%), neutropenia (81%), vomiting (15%), anorexia (17%), diarrhea (6%), and fatigue (11%). The authors concluded that docetaxel was active for gastric carcinoma and clinical trials of docetaxel in combination regimens were warranted. Furthermore, because of the promising data from this and additional studies conducted in Japan, docetaxel is approved for the treatment of gastric cancer in that country and in Korea.

Front-Line Therapy

Einzig and colleagues from the Eastern Cooperative Oncology Group (ECOG) studied docetaxel, 100 mg/m² every 3 weeks, in 41 patients with previously untreated advanced upper gastrointestinal carcinoma.[9] An objective response rate of 17% was attained, including two complete and five partial responses. Grade 4 neutropenia was reported in 88% of patients, and 46% of patients required a dose reduction following an episode of neutropenic fever. Reversible nonhematologic toxicities included grade 3/4 nausea, vomiting, diarrhea, stomatitis, fatigue, and peripheral neuropathy. The investigators concluded that docetaxel was active in adenocarcinomas of the upper gastrointestinal tract and suggested that further investigations should be conducted in multidrug combination regimens.

Mavroudis et al[10] conducted a phase II study to evaluate the efficacy and tolerability of docetaxel monotherapy with granulocyte colony-stimulating factor (G-CSF [Neupogen]) support as front-line therapy in patients with advanced gastric cancer. Docetaxel, 100 mg/m², was administered once every 3 weeks, together with G-CSF, 5 µg/kg on days 2 to 8 (to maximize dose intensity and reduce the incidence of febrile neutropenia). A total of 30 patients with advanced gastric carcinoma were enrolled, including 24 chemotherapy-naive patients and 6 patients who had received prior adjuvant chemotherapy following surgical resection. An overall response rate of 20% was observed, including one complete response and five partial responses. Two of the partial responses occurred in patients who had experienced progressive disease while on prior adjuvant chemotherapy. Disease stabilized in an additional seven patients (23%).

The median duration of response was 4.5 months, and the median Kaplan-Meier estimated probability of 1-year survival was 28%. Responses were observed at all sites of disease (including the primary tumor site) in patients with unfavorable histologic grade tumors, regardless of whether they had undergone surgical resection of the primary tumor. No unanticipated toxic effects were observed. The main toxicity was grade 3/4 neutropenia (36% of patients). Febrile neutropenia was reported in three cycles (2%), from three different patients (10%), and required hospitalization and intravenous antibiotics. Nonhematologic toxicities were generally mild to moderate and included grade 3 nausea and vomiting in two patients (6.6%), grade 3 diarrhea in one patient (3%), and grade 3 fatigue in one patient (3%). The docetaxel dose was reduced in nine cycles (7%), primarily because of neutropenia.

The authors concluded that a response rate of 20% classifies docetaxel among the most active chemotherapy agents for this disease. Two patients demonstrated a partial response to docetaxel after experiencing disease progression on primary, adjuvant chemotherapy treatment with FUP (5-FU, cisplatin [Platinol], and leucovorin) and FAM (5-FU, doxorubicin [Adriamycin], mitomycin [Mutamycin]) regimens, suggesting that docetaxel is, at least partially, non-cross-resistant to other agents commonly used for the treatment of gastric cancer. The authors stated that further studies incorporating docetaxel with other active drugs in combination regimens were warranted to improve palliation and possibly survival.

Docetaxel in Previously Treated Gastric Cancer Patients

Very few agents produce response rates greater than 15% as second-line chemotherapy for metastatic gastric cancer. Because of docetaxel’s considerable activity in front-line disease, several trials have assessed it as a single agent or in combination regimens for second-line gastric cancer (Table 2).[11-14,26]

Taguchi[11] reported the results of a phase II study that enrolled 44 patients with various advanced gastrointestinal cancers who were treated with docetaxel, 60 mg/m² every 3 or 4 weeks. Of 44 patients enrolled, 32 patients completed the scheduled course of treatment. Among 15 patients with gastric carcinoma, a partial response was observed in 3, for a response rate of 20%. All responding patients had previously demonstrated no response to prior chemotherapy. The most frequent adverse reactions included grade 3/4 leukopenia (75%) and neutropenia (92%). Nonhematologic toxicities were reported as acceptable. The authors concluded that docetaxel was a highly effective agent when used for the treatment of gastric cancer.

Vanhoefer et al[12] conducted an investigation of single-agent docetaxel as second-line chemotherapy in patients with documented disease progression following 5-FU-containing chemotherapy regimens. Patients were treated with docetaxel, 100 mg/m² IV as a 1-hour infusion every 3 weeks, along with oral dexamethasone prophylaxis. A total of 25 patients with measurable disease and documented progression after 5-FU-based regimens were evaluable for response and toxicity. An overall response rate of 20% was reported, including one complete response and four partial responses. Stabilization of disease was achieved in an additional eight patients (32%), resulting in an overall tumor growth control rate of 52%.

A median of four cycles of treatment (range: 1-8) were delivered. Short-lasting grade 4 neutropenia was the most common toxicity occurring in 60% of patients. Nonhematologic toxicities consisted of grade 3 neuropathy (8%), asthenia (8%), mucositis (4%), and diarrhea (4%). No cases of grade 4 nonhematologic toxicities were reported. The authors concluded that docetaxel was notably active in the second-line therapy for patients with metastatic gastric cancer following prior exposure to 5-FU-based regimens, and that it deserved further evaluation in combination chemotherapy regimens.

Graziano and colleagues conducted an investigation of weekly docetaxel for a similar group of advanced gastric cancer patients who failed a first-line, 5-FU-based regimen.[13] The regimen consisted of docetaxel, 36 mg/m² per week for 6 consecutive weeks, followed by 2 weeks of rest. All patients were treated with three doses of premedication that included dexamethasone, 8 mg at 12 hours and 1 hour before administration of docetaxel and again at 12 hours following docetaxel. A total of 21 patients were treated with weekly docetaxel. One patient completed two 8-week cycles, 18 patients completed one 8-week cycle, and two patients completed only 4 weeks of docetaxel treatment due to progressive disease. One patient showed a partial response to treatment and eight patients demonstrated stable disease.

None of the patients experienced grade 4 toxicities. Grade 3 toxicities included leukopenia in one patient, and leukopenia, thrombocytopenia, and dermatitis in another patient. The most common toxicity was grade 2 asthenia, reported in 90% of patients. The authors concluded that as salvage chemotherapy in patients with advanced gastric cancer, weekly docetaxel does not possess significant antitumor activity. However, the authors suggested that in the first-line setting, multidrug regimens including weekly docetaxel may prove effective.

Andre et al[14] combined docetaxel and epirubicin in patients with advanced gastric carcinoma who had failed previous treatment with 5-FU- and cisplatin-based chemotherapy regimens. Patients received epirubicin, 60 mg/m², followed 1 hour later by docetaxel, 75 mg/m². Chemotherapy cycles were repeated every 3 weeks until disease progression. A total of 25 patients were enrolled in the study. Among 23 patients with evaluable disease, 5 patients (22%) demonstrated a partial response and 7 patients (30%) demonstrated stable disease.

Mean duration of response was 29 weeks, and mean duration of disease stabilization was 22 weeks. Median progression-free survival and overall survival were 16 weeks and 29 weeks, respectively. The main toxicity was grade 3/4 neutropenia (28%) and febrile neutropenia (9%). Nonhematologic toxicities were mild. The authors concluded that these promising results deserved confirmatory second-line studies and evaluation in the first-line treatment setting.

Docetaxel-Based Combination Trials for Gastric Carcinoma

The standard chemotherapy regimens developed for gastric carcinoma include various combinations and schedules of drugs that are active as single agents (consisting of 5-FU, cisplatin, the anthracyclines doxorubicin and epirubicin [Ellence], and mitomycin). A logical investigational research step has been the addition of docetaxel to one or more of these agents (Table 3). [16-21] The reasons are several, beginning with the single-agent activity of docetaxel in gastroesophageal tumors. Secondly, a lack of cross-resistance between docetaxel and cisplatin, and 5-FU has been demonstrated in vitro,[15] and, as noted earlier, at least partial non-cross-resistance has been demonstrated clinically.[10] Finally, the toxicity profiles of docetaxel and agents such as cisplatin have little significant overlap.[16]

Roth and colleagues of the Swiss Group for Clinical Cancer Research and the European Institute of Oncology[16] studied the combination of docetaxel and cisplatin in patients with unresectable or metastatic gastric carcinoma in a multicenter phase I/II trial that evaluated two doses of docetaxel in 48 patients. Docetaxel, 85 or 100 mg/m², plus cisplatin, 75 mg/m², were administered once every 21 days. Because of good tolerance in the first six patients treated with docetaxel, 85 mg/m², the dose was increased to 100 mg/m². In five patients treated at this level, two episodes of febrile neutropenia and one episode of grade 3 mucositis were observed. Therefore, the remaining patients received docetaxel, 85 mg/m². However, all patients were included in the final safety and efficacy analysis. Among 48 patients studied, two had a complete response and 25 had a partial response for an overall response rate of 56%. An additional 12 patients had stabilization of their disease for 9 weeks or more (three cycles). Of note, 37% of responders met the partial response criteria after just two cycles of therapy.

The median progression-free survival was 6.6 months, and the median overall survival was 9 months. A median of five treatment cycles were administered per patient, with 230 cycles of treatment administered overall. Despite the development of grade 3/4 granulocytopenia in 81% of patients (56% of cycles), only nine episodes of febrile neutropenia were reported in eight patients (19%), including two episodes in patients treated with docetaxel at the 100 mg/m² dose. Nonhematologic toxicities were infrequent, with grade 3/4 events (fatigue, mucositis, diarrhea, and nausea/vomiting) all occurring in less than 10% of patients.

The investigators concluded that the docetaxel/cisplatin combination is a very potent and well-tolerated regimen for gastric carcinoma. They suggested that this active two-drug regimen could be used as the basis for the development of more potent combinations that incorporate three or more agents in gastric cancer.

The same investigators[17] therefore conducted a phase I/II trial, adding the continuous infusion of low-dose 5-FU to the docetaxel and cisplatin combination. The dose range of 5-FU was 200 to 300 mg/m² per day administered as a continuous intravenous infusion for 2 out of 3 weeks. The dose range of cisplatin was 60 to 75 mg/m² and the dose range of docetaxel was 70 to 85 mg/m², with both drugs administered on day 1 of a 3-week cycle. A total of 43 advanced gastric carcinoma patients were treated. An overall response rate of 50% was observed. The investigators concluded that 5-FU can be safely added to full-dose docetaxel (85 mg/m²) and cisplatin (75 mg/m²), and they continue to investigate this regimen in advanced gastrointestinal tumors.

Kettner et al[18] reported the combined results from two phase II trials (a single-center trial and a multi-institutional trial) in patients with chemotherapy-naive gastric carcinoma treated with docetaxel, 75 mg/m², and cisplatin, 75 mg/m², administered on day 1 of an every 21-day cycle. At the time of this report, 39 patients were enrolled in the single-center trial and 76 patients were enrolled in the multi-institutional trial. A combined total of 85 patients from both studies were evaluable for response, and an overall response rate of 36% was reported, with seven patients achieving a complete response.

The single-center study reported a median survival of 10.4 months, and, at the time of this report, the multi-institutional study reported an estimated median survival of 9 months. Toxicity assessment from a total of 96 patients revealed the major toxicities to include grade 3/4 myelotoxicity (18%), grade 3 gastrointestinal toxicities (8%), and grade 3 neurotoxicity (1.6%). The high activity level prompted the investigators to initiate a phase III comparison of docetaxel/cisplatin vs a standard regimen of 5-FU/cisplatin.

Triple-Drug Regimens

Addition of 5-FU

Ajani et al reported findings from a randomized phase II study in untreated patients with advanced gastric or gastroesophageal junction adenocarcinoma.[19] Patients were randomized to treatment with either TC (docetaxel [Taxotere], 85 mg/m² on day 1; and cisplatin, 75 mg/m² on day 1, every 3 weeks) or TCF (docetaxel [Taxotere], 75 mg/m² on day 1; cisplatin, 75 mg/m² on day 1; and 5-FU, 750 mg/m² per day on days 1 to 5, every 3 weeks). Data on 70 patients were reported. Among 29 patients treated with the TC combination, a 45% partial response rate was observed in comparison to a 52% partial response rate in 31 patients treated with the TCF combination. The three-drug regimen resulted in a slightly higher incidence of toxicities. In particular, the nonhematologic toxicities, including diarrhea (5% vs 1%), nausea (8% vs 1%), vomiting (7% vs 1%), and stomatitis (16% vs 0%) were more frequent with the TCF regimen as compared with the TC regimen, respectively. The TC regimen was associated with a higher incidence of grade 3/4 neutropenia (72%) as compared with the TCF regimen (50%); however, the incidence of febrile neutropenia was similar for the TC (7%) and TCF (8%) regimens, respectively. Upon review of data in all 158 patients enrolled in the study, the data monitoring committee selected the three-drug TCF regimen as the experimental arm of an ongoing phase III trial, comparing it with the widely used control arm of 5-FU/cisplatin.

Constenla et al[20] reported results from a study of a combination of docetaxel, 75 mg/m² or 100 mg/m² on day 1, with 5-FU, 1,800 mg/m², and leucovorin, 500 mg/m², both administered over 24 hours on days 1, 8, and 15 of an every-28-day cycle. A total of 26 patients were enrolled, with six patients (defined as frail) treated with docetaxel, 75 mg/m², and 20 patients treated with docetaxel, 100 mg/m². The overall response rate was 22%, and three patients (17%) achieved a complete response. An additional 10 patients (58%) demonstrated stable disease. Due to grade 4 neutropenia in 17% of cycles, affecting 52% of patients, the authors suggested that the addition of G-CSF could be useful. The authors concluded that a significant number of complete responses (17%) were obtained, and most patients (80%) obtained a clinical benefit (complete or partial response, or stable disease) despite a modest 22% overall response rate.

The improved safety profile of weekly docetaxel and the demonstration of synergy between docetaxel and 5-FU led Chun and colleagues[21] to treat elderly patients with cancer of the stomach and distal esophagus with weekly docetaxel and low-dose 5-FU by continuous infusion. A total of 15 patients aged 70 years or older were enrolled and treated with a combination of docetaxel, 25 mg/m²/wk, and continuous-infusion low-dose 5-FU, 150 mg/m²/d, for 14 days at 3-week intervals. In 14 patients evaluable for response, 1 complete response, 11 partial responses, and 1 minor response were observed. Toxicities were reported as mild and reversible in the majority of patients. Two patients experienced grade 3/4 neutropenia and mucositis. The authors reported an excellent safety profile and high level of clinical activity of the regimen in elderly patients with cancer of the stomach and distal esophagus.

Wadler et al reported results of a randomized phase II study in which patients with untreated advanced gastric carcinoma were randomized to receive either 5-FU, intravenous hydroxyurea, and interferon-alpha, or doxorubicin plus docetaxel.[22] Accrual to the study was terminated early because minimum or no responses were observed with either regimen. The investigators concluded that the substantial tumor burdens in this patient population may have contributed to the lack of activity of the regimens used in this study.

Addition of Irinotecan

A recent report discussed the addition of irinotecan (CPT-11, Camptosar) to the docetaxel/cisplatin combination.[23] Fuchs et al[23] reported a phase I study of the three-drug combination with docetaxel at 25 or 30 mg/m², cisplatin at 22 or 30 mg/m², and irinotecan at 25 to 55 mg/m², all administered on a weekly basis for 2 consecutive weeks of a 3-week cycle. At the time of this report, 15 patients have been enrolled in the study, including four patients with gastric cancer and seven patients with esophageal cancer. The preliminary results suggest activity in esophageal and gastric cancer. The investigators concluded that administration of the drugs on a weekly basis was tolerable and provides a schedule that can maximize synergy between the three drugs.

Enrech and colleagues are conducting a phase II study of the docetaxel/irinotecan combination in patients with locally advanced or metastatic gastric cancer. At the time of this report, 14 patients have been enrolled and treated with docetaxel, 60 mg/m², and irinotecan, 250 mg/m², both administered on day 1 of a 21-day cycle. In 52 cycles of therapy administered to date, grade 3/4 toxicities included neutropenia (12%), leukopenia (8%), asthenia (6%), anemia (2%), nausea/vomiting (2%), and diarrhea (2%). In four patients evaluable for efficacy, two achieved stable disease.

The authors’ preliminary analysis indicates that the every-3-week administration of docetaxel and irinotecan appears to be feasible, and patients continue to accrue to the study. Taken together, the preliminary information suggests that the docetaxel and irinotecan (plus or minus cisplatin) combinations are promising both for safety and efficacy, and suggest that this type of regimen may be of significant interest in the future treatment of gastric and esophageal cancers.

Sequential Docetaxel in Gastric Cancer

Cascinu and colleagues reported the results of a phase II investigation of the sequential addition of docetaxel following an intensive weekly PELF regimen (cisplatin [Platinol], epirubicin, 5-FU, leucovorin, glutathione) in patients with chemotherapy-naive relapsed or metastatic gastric cancer.[25] Eligible patients received eight weekly administrations of chemotherapy with cisplatin, 40 mg/m²; epirubicin, 35 mg/m²; 5-FU, 500 mg/m²; leucovorin, 250 mg/m²; and glutathione, 1.5 g/m2. Prophylactic G-CSF, 5 µg/kg, was administered on nonchemotherapy days during the PELF chemotherapy phase. Patients demonstrating a partial response or stable disease were subsequently treated with docetaxel, 100 mg/m² every 3 weeks for three cycles. In 40 patients treated with weekly PELF, three patients (7.5%) achieved a complete response, 13 patients (32.5%) demonstrated a partial response, and 21 patients demonstrated stable disease. The 13 partial responders and 21 stable disease patients subsequently received sequential docetaxel therapy. After therapy with three cycles of docetaxel, an improved outcome was achieved in 26.5%; two PELF partial responders achieved a complete response (6%), and seven patients with stable disease on PELF achieved a partial response (20.5%). An overall response rate to the PELF/docetaxel regimen was 57.5%, with a median time to progression of 7 months and a median overall survival of 12.6 months.

All 34 patients begun on sequential docetaxel completed the planned three cycles of therapy, with dose delay by 1 week for hematologic recovery in 45% of cycles. While prophylactic G-CSF was not routinely administered during the docetaxel phase, it was used to maintain the planned dose of therapy in 10 patients who experienced grade 3/4 neutropenia. Adverse events that occurred during the 102 cycles of docetaxel therapy included grade 3/4 neutropenia (10%), thrombocytopenia (19%), and grade 3 nausea and vomiting (15%).

The authors concluded that enhanced tumor shrinkage was gained in patients treated with sequential docetaxel following PELF induction therapy and suggested that the PELF/docetaxel sequential combination represents an interesting evolution of the PELF regimen. Their sequential use demonstrated a favorable toxicity-to-efficacy ratio and deserves further investigation in the palliative or neoadjuvant setting.

Docetaxel in Carcinoma of the Esophagus

Platinum- and 5-FU-based chemotherapy regimens remain the standard first-line therapy in patients with metastatic esophageal cancer. However, no clear standard exists for patients who fail first-line therapy. Metges et al[26] treated 31 patients who failed previous treatment on a platinum-based regimen with docetaxel, 100 mg/m² every 3 weeks. Twenty-one of 31 patients had squamous cell carcinoma of the esophagus, and the remaining 10 patients had adenocarcinoma. All patients were evaluable for toxicity, and 25 patients were evaluable for response after completing at least three cycles of therapy. A total of 113 cycles of therapy were administered with 18.5% of cycles delivered at a reduced dose because of hematologic toxicity. An overall response rate of 28% was reported, with three complete responses and four partial responses. An additional 10 patients achieved stable disease (Table 2).

Grade 3/4 neutropenia was reported in 64.5% and febrile neutropenia was reported in 38.7%, resulting in two deaths from sepsis. The authors concluded that docetaxel was highly effective for previously treated metastatic esophageal carcinoma, and suggested that further studies in locally advanced disease are warranted.

Mauer et al[27] reported a phase II study in patients with locoregional carcinoma of the esophagus or proximal stomach who received induction chemotherapy with docetaxel, 75 mg/m², plus cisplatin, 75 mg/m², on day 1 every 21 days for three cycles. This regimen was followed by combined chemoradiotherapy with weekly docetaxel, 20 mg/m², plus daily radiotherapy for 5 weeks (total radiation of 50 Gy) for patients with resectable cancer and for 7 weeks (total radiation of 70 Gy) in patients with unresectable cancer. The responses obtained with chemoradiotherapy included 14 complete responses and 15 partial responses. For patients receiving neoadjuvant therapy, an overall response rate of 58% was attained. In 32 patients who underwent surgery, 14 displayed a pathologic complete response and 10 had only microscopic cancer in the specimen.

During induction chemotherapy, grade 3/4 toxicity included vomiting, leukopenia, and reversible azotemia. During chemoradiotherapy, the predominant toxicity noted was esophagitis. The authors concluded that this large phase II study confirms the activity and tolerability of the docetaxel-based regimen. The high rate of pathologic complete responses indicates encouraging local control as the result of treatment. These results provide further incentive to pursue docetaxel in the combined-modality setting in patients with upper gastrointestinal cancers.

Roth et al[28] reported the results of a neoadjuvant phase I/II study with the combination of docetaxel, cisplatin, and 5-FU in patients with locoregional carcinoma of the esophagus. A 2-week course of chemotherapy was followed by hyperfractionated radiotherapy (up to 62.4 Gy) alternating with 5-FU. Chemotherapy consisted of docetaxel, 30 or 35 mg/m² on days 1 and 8; cisplatin, 60 mg/m² on day 1; and 5-FU, 200 mg/m²/d on days 1 to 14. Sandwiched between radiotherapy treatments, 5-FU treatment was repeated on days 29 to 42 and on days 57 to 70. Results in 19 patients were reported. Among 12 patients taken to surgery, eight (66%) achieved a pathologic complete response. The seven remaining patients were not operated on.

Neutropenia (10%), febrile neutropenia (21%), and esophagitis (31%) were reported as the predominant toxicities. The authors concluded that the regimen was feasible and toxicity was acceptable with docetaxel at 30 mg/m², which is the recommended dose for further investigation. The treatment program resulted in a high pathologic complete response rate that justifies confirmation in a phase II study.

Conclusions

It is evident, based upon the review presented here, that much enthusiasm exists in pursuing investigative approaches that incorporate docetaxel for patients with upper gastrointestinal tumors. Docetaxel has emerged as an active agent for advanced gastric and esophageal cancers, both as a single agent and in combination regimens. As a single agent in the front-line treatment of gastric cancer, docetaxel may be classified among the most active agents for the disease, with overall response rates of 17% to 24%. Docetaxel has also proven effective, with response rates in the 20% to 22% range in the second-line setting for patients who failed prior platinum- and 5-FU-based regimens, offering an extended armamentarium in the treatment of gastric tumors.

When combined with cisplatin for the front-line treatment of gastric cancer, response rates are comparable with results obtained using three- and four-drug regimens, and treatment is tolerable. The findings offer a unique opportunity to utilize docetaxel- and cisplatin-based combinations in the preoperative (neoadjuvant) setting, where the potential for higher response rates to downstage the cancer are desirable.

The successful addition of 5-FU to the docetaxel/cisplatin combination has been reported in several trials, and the triple-drug combination is now being tested in a randomized phase III trial in comparison with an established standard regimen. Early data discuss the combined use of docetaxel and irinotecan, with or without cisplatin, which may provide an interesting regimen employing two newer agents. A further innovative use of docetaxel has been its sequential addition to the weekly PELF regimen for advanced gastric cancer. The results of a phase II study demonstrate the ability to enhance tumor control and improve response rates with such an approach.

Finally, docetaxel is being pursued for its radiosensitizing activity as an agent for use in chemoradiotherapy protocols for patients with gastric and esophageal carcinomas. In the future, research efforts will be devoted to identifying markers for predicting response. In this manner, docetaxel can be selectively administered to those patients most likely to benefit from its therapy.

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